Excessive alcohol consumption is a significant public health burden that affects 30% of the population at some point in their lives, contributes to liver and cardiovascular disease, obesity, diabetes and cancer, and costs $24.6 billion in health care and $161.3 billion in lost productivity annually. Even the moderate social drinking in 50%-70% of US adults is associated with health risks. Many studies in humans have consistently shown that a delay in circadian timing is associated with more alcohol use and abuse, even after controlling for factors such as pubertal development, age, sex, race, socioeconomic status, and educational level. Delays in circadian timing, even small ones, negatively affect mood, sleep, and reward function, which can drive further alcohol consumption. The central circadian pacemaker regulates the timing of circadian rhythms, but is adjusted daily by light signaling from intrinsically photosensitive retinal ganglion cells (ipRGCs). Research in rodents has demonstrated that alcohol acts directly on the central circadian pacemaker, altering circadian phase shifts to light. However, the effect of alcohol on ipRGC responses to light remains to be investigated. This application answers PA-12-177, which calls for mechanistic studies in humans...to determine how alcohol interferes in circadian resetting in response to environmental stimuli...with ultimate goal of improved understanding of causes and treatments for alcoholism. We propose to measure the effects of acute and chronic alcohol on ipRGC responses to light in humans, using a novel and reliable photostimulating technology in 64 light (32 men, 32 women) and 64 heavy (32 men, 32 women) social drinkers. In a within-subjects, double-blind, placebo-controlled, randomized design (26 day protocol), we will assess ipRGC responses at baseline and before and after an intoxicating dose of alcohol (vs. placebo). We will also examine how ipRGC responses predict baseline circadian timing, and circadian phase shifts to bright light by measuring the dim light melatonin onset. Finally, we will assess how baseline ipRGC activity and circadian timing relate to baseline mood, sleep quality and reward function, and to the subjective response to an acute dose of alcohol. Aim 1 is to determine the extent to which a heavy alcohol drinking pattern (vs. lighter drinking) alters light-evoked ipRGC responses and circadian timing. Aim 2 is to determine the extent to which an intoxicating dose of alcohol (vs. placebo) alters ipRGC responses and circadian shifts to light. Aim 3 is to determine the extent to which ipRGC responses predict circadian timing in light and heavy drinkers. In exploratory aims, we will assess: (1) if the effect of alcohol on ipRGC responses and circadian timing are associated with sex (men, women) and subjective responses to alcohol and (2) the relationships among baseline ipRGC responses, circadian timing, mood, sleep, reward function, and alcohol use. The proposed research will provide a critically needed mechanistic understanding of how alcohol impacts photoentrainment and circadian timing in humans, and how these influence mood, sleep, and reward function, which in turn can predict alcohol use/misuse.